tbuckley/cabot-search huggingface dataset:
Application of circulating tumor DNA for prediction and surveillance of tumor recurrence after liver transplantation: A pilot study.
Authors: Ao Huang, De-Zhen Guo, Xuan Zhang, Ying Sun, Xin Zhang, XiuTao Fu, Yupeng Wang, Guo-Huan Yang, Qiman Sun, Yifeng He, Kang Song, Xiao-Wu Huang, Wei-Ren Liu, Zhen-Bing Ding, Ying-Hong Shi, Jia Fan, Jian Zhou
Journal: Journal of Clinical Oncology (2022)

e16149 Background: Emerging data suggest that circulating tumor DNA (ctDNA) could detect minimal residual disease (MRD) and reflect tumor recurrence after radical resection in hepatocellular carcinoma (HCC). However, most reported ctDNA measurements are based on hotspot mutations and their predictive value in liver transplantation (LT) are still undetermined. We conducted a pilot study investigate ctDNA fingerprint as the detection marker of MRD in HCC patients undergoing LT. Methods: We enrolled 74 patients in HCC and monitored their ctDNA changes along the course of treatment at both pre- and post-operation by serial sampling of peripheral blood. All of the patents were treated by LT, and their ctDNA variations were used to assess the recurrence. We analyzed the correlation between ctDNA levels and recurrence-free survival (RFS) of the patients. Results: We monitored the ctDNA value of each patient before and after LT and found that the ctDNA-positive group was associated with higher recurrence rate (31.7% vs 11.5%), and has a shorter RFS than that of the ctDNA-negative group at baseline (preopreation) (HR, 3.25; CI 95% 1.18-8.97; p = 0.019). The conclusion also stands in patients at first timepoint follow-up after LT (postoperation) (recurrence rate, 46.2% vs 21.3%; HR, 4.26; CI 95% 1.62-11.2; p = 0.010). Moreover, changes of ctDNA were associated with RFS during the course after LT, both the ctDNA-decreased group and ctDNA-negative group have favorable clinical benefit than ctDNA-increased group. Conclusions: This study confirming the association between baseline levels of ctDNA and RFS in HCC undergoing LT. More importantly, it suggests the change of ctDNA level in plasma is a promising biomarker of MRD detection and patient prognosis in early HCC.
Building a multidisciplinary consortium in Iowa to advance genetic counseling and testing in patients with cancer.
Authors: Sandra Megally, matthew Obinna nwaneri, Joseph Kim, Limaya Atembina, Lorna Lucas, Lu Anne Bankert
Journal: Journal of Clinical Oncology (2022)

10609 Background: As cancer clinicians develop increasingly complex treatment plans, the results from somatic and/or germline tests are guiding personalized treatment decisions. Many patients with cancer do not get optimal genetic counseling/testing when indicated. To ensure that cancer clinicians are following the latest clinical recommendations around genetic counseling/testing, the Iowa Oncology Society (IOS), working in collaboration with the Association of Community Cancer Centers (ACCC), developed a multiphase initiative to inform quality improvement (QI) opportunities. Methods: In 2021, IOS launched a multidisciplinary consortium to advance genetic counseling and testing in oncology. Engaging a diverse group of stakeholders, IOS held a focus group to explore the current landscape, conducted three educational lunch and learn sessions, produced a podcast, and hosted a working group meeting. These meetings and activities were designed to explore ways to overcome common barriers in care delivery and identify effective practices to coordinate cancer genetic counseling and testing in clinical practice. Results: Through this initiative, IOS identified several key improvement opportunities for cancer clinicians treating patients in Iowa. Since 43 percent of Iowa’s population is rural, this initiative also identified practical strategies for oncology practices in low-resource areas. The following insights and suggestions were generated from this initiative: 1) Cancer programs may implement creative ways to collect patient history and screen patients for hereditary cancer syndromes. 2) Clinicians may use more effective education materials when referring patients for genetic counseling. 3) Clinicians may clarify language/communication to reduce confusion about somatic vs. germline test results. 4) Cancer programs may form partnerships with local genetic counselors and/or organizations that offer telehealth services. IOS summarized these ideas and disseminated education and resources to guide cancer clinicians in assessing and improving their own practices. Conclusions: This multiphase initiative represents a framework for a state oncology society to engage other stakeholders and lead interdisciplinary efforts to improve care for patients with cancer. As the landscape of genetic counseling evolves, IOS supports legislative efforts aimed at having Medicare recognize certified genetic counselors (CGCs) as healthcare providers. IOS plans to build on this initial work to advance cancer genetic counseling and testing throughout the state by developing additional programming in 2022.
DIPG-31. Prognostic and predictive biomarkers of response in children and young adults with H3K27M-altered diffuse intrinsic pontine glioma: results from a multi-center, interventional clinical trial (PNOC003)
Authors: Cassie Kline, Payal Jain, Lindsay Kilburn, Erin Bonner, Nalin Gupta, John Crawford, Anu Banerjee, Roger Packer, Javier Villanueva-Meyer, Tracy Luks, Yalan Zhang, Madhuri Kambhampati, Jie Zhang, Sridevi Yadavilli, Adam Kraya, John Kuhn, Winnie Liang, Sara Byron, Michael Berens, Annette Molinaro, Michael Prados, Adam Resnick, Sebastian Waszak, Javad Nazarian, Sabine Mueller
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal brain tumor. Herein, we report on novel prognostic and predictive genomic biomarkers identified in PNOC003, a multi-center precision medicine trial for children and young adults diagnosed with DIPG. METHODS: Patients aged 3-25 years were enrolled on PNOC003 based on radiographic diagnosis of DIPG. Pre-treatment tumor biopsies were analyzed using tumor-normal whole-exome sequencing and mRNA-tumor sequencing to determine biology-informed, multi-agent therapy following radiation therapy (RT). Whole-genome sequencing was performed as an exploratory study aim. Genomic biomarkers were investigated to identify predictors of RT response and overall survival (OS) in patients with confirmed H3K27M-altered DIPG. Prognostic biomarkers were verified in a retrospective, H3K27M-altered diffuse midline glioma cohort (n=22) from the Children’s Brain Tumor Network (CBTN). RESULTS: Thirty patients enrolled on PNOC003 met molecular criteria for H3K27M-altered DIPG. TP53 was the most frequently altered driver gene (73%). Somatic alterations in PTEN&amp;gt;TP53&amp;gt;PDGFRA were independently associated with OS (P&amp;lt;0.05, in order of negative impact on survival). TP53 mutations associated with worse OS (TP53mut 11.1 mo [95% CI 8.7, 14]; TP53wt 13.3 mo [95% CI 11.8, NA]; P=3e-2), chromosomal instability (P=3e-3), and resistance to RT (P=6e-4). Moreover, loss of chromosome 10q, encoding tumor suppressor PTEN, was associated with worse OS, co-occurred with PTEN alterations, biallelic PTEN inactivation and loss of gene expression. The combination of TP53 alterations and loss of 10q/PTEN in H3K27M-altered DIPG was associated with the worst OS in a combined PNOC003 and CBTN cohort (TP53mut/10qdel, n=14, OS 8.4 mo [95% CI 7.4, 15.8]; TP53mut/10qwt, n=20, OS 13.1 mo [95% CI 10.1, 17.2]; TP53wt/10qwt, n=14, OS 15.5 mo [11.8, 29.4]; P=2e-3). CONCLUSION: PNOC003, a tissue-driven clinical trial, provided insights into prognostic and predictive genomic biomarkers and informed a novel molecular tumor classification system for H3K27M-altered DIPGs.
De novo reconstruction of cell interaction landscapes from single-cell spatial transcriptome data with DeepLinc
Authors: Runze Li, Xuerui Yang
Journal: Genome biology (2022)

Abstract Based on a deep generative model of variational graph autoencoder (VGAE), we develop a new method, DeepLinc (deep learning framework for Landscapes of Interacting Cells), for the de novo reconstruction of cell interaction networks from single-cell spatial transcriptomic data. DeepLinc demonstrates high efficiency in learning from imperfect and incomplete spatial transcriptome data, filtering false interactions, and imputing missing distal and proximal interactions. The latent representations learned by DeepLinc are also used for inferring the signature genes contributing to the cell interaction landscapes, and for reclustering the cells based on the spatially coded cell heterogeneity in complex tissues at single-cell resolution.
Frailty status predicts worse postoperative outcomes and long-term oncologic outcomes in patients treated with partial nephrectomy
Authors: G. Rosiello, G. Fallara, A. Martini, G. Cignoli, G. Basile, G. Colandrea, G. Baiamonte, W. Cazzaniga, L. Nocera, A. Nini, I. Rowe, D. Canibus, G. Musso, F. Cei, M. Romani, C. Giancristofaro, A. Briganti, R. Bertini, F. Montorsi, A. Salonia, A. Larcher, U. Capitanio
Journal: European Urology (2022)
Left atrial volume index and outcome after transcatheter edge‐to‐edge valve repair for secondary mitral regurgitation
Authors: Christos Iliadis, Daniel Kalbacher, Philipp Lurz, Aniela Monica Petrescu, Mathias Orban, Tania Puscas, Laura Lupi, Laura Stazzoni, Gustavo Pires‐Morais, Benedikt Koell, Christian Besler, Tobias Friedrich Ruf, Lukas Stolz, Noemie Tence, Marianna Adamo, Cristina Giannini, Cláudio Guerreiro, Martin Hellmich, Stephan Baldus, Niklas Schofer, Holger Thiele, Ralph Stephan von Bardeleben, Jörg Hausleiter, Nicole Karam, Marco Metra, Anna Sonia Petronio, Bruno Melica, Roman Pfister
Journal: European Journal of Heart Failure (2022)

To investigate the role of left atrial volume index (LAVi) in patients with secondary mitral regurgitation (SMR) undergoing transcatheter edge-to-edge mitral valve repair (TEER).Outcomes were evaluated in SMR patients of a European multicentre registry according to baseline LAVi. Main analysis was performed for all-cause mortality; residual mitral regurgitation (MR) and New York Heart Association (NYHA) class improvement were analysed for patients available. A total of 1074 patients were included with a median LAVi (interquartile range) of 58 ml/m2 (46-73). Postprocedural reduction of MR grade to ≤2+ was similar across LAVi quintiles, ranging 91%-96% (p = 0.26). Symptomatic benefit (≥1 NYHA class improvement) also did not differ by LAVi quintiles (61%-68% of patients) (p = 0.66). The risk of mortality increased by 23%-42% in the four upper quintiles compared to the bottom quintile (LAVi <42 ml/m2 ). The hazard ratio (HR) of mortality was 1.35 (95% confidence interval [CI] 1.02-1.78, p = 0.035) associated with a LAVi >42 ml/m2 , which was attenuated after multivariable adjustment (HR 1.18, 95% CI 0.83-1.67, p = 0.36). A significant interaction was found for MR severity and pulmonary hypertension, with an increased risk of death associated with enlarged LAVi in patients with inframedian effective regurgitant orifice area (HR 1.99, 95% CI 1.06-3.74, p = 0.032) and in patients with systolic pulmonary pressure ≤50 mmHg (HR 1.67, 95% CI 1.02-2.75, p = 0.042) in multivariable analysis.Procedural success and symptomatic benefit were high throughout the whole range of LAVi. The prognostic impact of left atrial enlargement was relevant in patients with less severe SMR and without pulmonary hypertension, reinforcing the need to identify patients in the early course of backward congestion to achieve good long-term outcome after TEER.
Biomarker associations of immune checkpoint inhibitor versus chemotherapy effectiveness in first-line metastatic endometrial carcinomas: A real-world study.
Authors: Alessandro Santin, Ryon Graf, Kunal J. Shah, Andrew David Kelly, Natalie Danziger, Douglas I. Lin, Geoffrey R. Oxnard, Julia Andrea Elvin
Journal: Journal of Clinical Oncology (2022)

5596 Background: Limited evidence exists comparing outcomes of single-agent anti-PD1 immune checkpoint inhibitors (ICPI) vs. chemotherapy in the 1 st line among metastatic endometrial carcinoma (mEC) patients. dMMR, MSI status, and Tumor Mutational Burden (TMB) have been characterized as predictive biomarkers of ICPI response in many solid tumors, including mEC. We sought to evaluate ICPI vs. chemotherapy effectiveness in 1st line mEC, stratified by TMB ≥ 10 mut/MB and MSI as assessed by next-generation sequencing. Methods: Following a prespecified analysis plan, this study used the nationwide (̃280 US cancer clinics) de-identified, EHR-derived, Flatiron Health-Foundation Medicine mEC clinico-genomic database (FH-FMI CGDB), with tissue CGP between 1/2011 - 6/2021. Cohort inclusion criteria: recurrent mEC patients with stage I-III at original diagnosis, 1 st line ICPI or platinum chemotherapy treatment with TMB and MSI assessments available. Adjusted hazard ratios (aHR) from multivariable Cox proportional hazard models were utilized for time to next treatment (TTNT) and overall survival (OS) comparisons between 1L chemotherapy and 1L ICPI from start of 1L treatment stratified by TMB (≥ 10 vs. &lt; 10) and adjusted for ECOG, BMI, and stage at diagnosis. Results: Among the 1 st line cohort, patients received either Chemotherapy (n = 139, 87%) or first-line ICPI (n = 20, 13%). While the overlap between the TMB ≥ 10 (n = 46) population and MSI-H (n = 39) populations was high, with 38/46 (83%) of TMB ≥ 10 classified as MSI-H and 38/39 (97%) of MSI-H with a TMB ≥ 10, there were also 8 (17%) TMB ≥ 10 patients who were MSS. TMB ≥ 10 was associated with more favorable TTNT (aHR: 0.11 [0.03 - 0.44]) and OS (aHR: 0.1 [0.01 - 0.82]) on single-agent ICPIs vs. chemotherapy; however, TMB &lt; 10 patients exhibited no observed differences in TTNT (aHR: 1.66 [0.79 - 3.48]) or OS (aHR: 1.79 [0.66 - 4.8]) between treatments. MSI-H pts were associated with more favorable TTNT (aHR: 0.1 [0.02 - 0.39]) and OS (aHR: 0.1 [0.01 - 0.86]) on single-agent ICPIs over chemotherapy; however, MSS pts did not observe differences in TTNT (aHR: 1.5 [0.65 - 3.5]) or OS (aHR: 2.14 [0.63 - 7.26]) between ICPI vs. chemotherapy. Conclusions: Recurrent 1 st line mEC patients with TMB ≥ 10 and/or MSI-H exhibit more favorable outcomes on single-agent ICPI than standard chemotherapy in real-world settings. These findings warrant prospective randomized validation. Future studies should assess the utility of a combined biomarker approach across TMB and MSI status to identify the broadest group of patients who might benefit from ICPI.
Impact of renal cell carcinoma histological variants on recurrence after partial nephrectomy: A multi-institutional, prospective study (UROCCR study 82)
Authors: T. Tabourin, U. Pinar, J. Parra, C. Vaessen, C-K. Bensalah, F. Audenet, P. Bigot, C. Champy, J. Olivier, F. Bruyere, D. Nicolas, P. Paparel, B. Parier, X. Durand, H. Lang, N. Branger, J-A. Long, M. Durand, T. Waeckel, T. Charles, O. Cussenot, E. Xylinas, J-C. Bernhard, M. Roupret
Journal: European Urology (2022)
Regorafenib third-lined therapy in advanced GISTs: A single center analysis based on different genotypes.
Authors: Sile Chen, Yanzhe Xia, Shaohua Yang, Yan Qian, Ertao Zhai, Shaoqing Huang, Yihang Shi, Yulong He, Shirong Cai, Xinhua Zhang
Journal: Journal of Clinical Oncology (2022)

11537 Background: The relationship between primary and secondary mutational status and efficacy of regorafenib in third-line therapy on GISTs is yet clear. Methods: From Jun 2017 to Dec 2021, a total of 62 patients with advanced GIST refractory to imatinib and/or sunitinib were enrolled in this study from the First Affiliated Hospital, Sun Yat-sen University. Results: Primary mutational was most common in KIT exon 11(40/62, 64.5%), followed by exon 9 (19.4%), exon 17 (4.8%). Six cases (9.7%) belonged to SDH deficiency and one case (1.6%) was NF1-associated GISTs. Before receiving treatment of regorafenib, specimens obtaining for secondary mutations were as follows: 39 cases from surgery，12 from core-needle biopsy; ctDNA alone was performed in 9 cases and 2 patients refused to secondary mutational test. Excluding 6 patients with SDH deficiency, 14 patients (25.8%) had mutations in exon 11+13, 15 (27.7%) in exon 11+17, 7 (13.0%) in exon 9+17, 4 (7.4%) in exon 11+13+17. Exon 11 + 18, exon 11 + 13 + 18, exon 11 + 13 + 17 + 18, exon 9 + 16, exon 11 + 17 + 18 and NF-1 were found in 1 case, respectively (1.9%). Eight (14.7%) patients with primary KIT mutation were not detected any secondary mutation（2 nd -not-detected）. There was no complete response, 4 of partial response (4/54, 7.4%), 27 of stable disease (50.0%). Progression disease was seen in 23 patients (42.6%) and 8 were not applicable (no assessable lesion) to imaging response assessment due to R0/1 surgery before using regorafenib. The median follow-up time was 19.0 months. The median progression-free survival (mPFS) was 5.4 months (0.2-29.1 months) and the median overall survival (mOS) was 20.3 months (0.2-37.0 months). For primary mutation analysis, it was found that SDH-deficient patients had longer mPFS (29.1 months) than those with mutations in exon 9 or exon 11 (5.4 and 4.8 months, respectively; P= 0.013). In terms of secondary mutations, patients with activation loop mutations (exon 17+18) showed both longer mPFS (7.3 months vs 1.9 months, P= 0.001) and longer mOS (20.3 months vs 7.7 months, P= 0.059) than those patients with non-activation loop mutations. Not any specific or new adverse reaction was found in all patients. By Cox-regression analysis, response to regorafenib and mutational status were independent predictors of PFS，response to regorafenib was also an independent predictor of OS. Conclusions: Regorafenib seems to have better treatment efficacy in GIST patients with SDH deficiency compared to those with primary KIT mutations, and better with secondary mutations in activation loop than those with non-activation loop mutations. It is necessary to carry out clinical research for later-line treatment choice based on different genotypes for imatinib-resistant GISTs.
Decreased bile acid metabolism and association with prognosis reflecting microbiome in tumor microenvironment involved in cancer cell proliferation in breast cancer.
Authors: Rongrong Wu, Irene Yu, Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Takashi Ishikawa, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2022)

e12539 Background: Bile acids are metabolized by the gut microbiome and are involved in fat absorption. Contrary to their carcinogenic role in gastrointestinal cancers, bile acids have been reported to inhibit cancer cell proliferation in breast cancer. We hypothesized that activation of bile acid metabolism is associated with a better prognosis based on previous reports regarding the antitumor effects of bile acids in breast cancer cells. Methods: A total of 6050 patients from three large open primary breast cancer cohorts (GSE96058, METABRIC, and TCGA) were analyzed by bile acid metabolism scores calculated by gene set variation analysis, and the association with the microbiome of the breast cancer tumor microenvironment in TCGA was also investigated. Results: We found that disease free, disease specific and overall survival was significantly improved in the high bile acid metabolism group, which was validated by three large breast cancer cohorts. However, apoptosis, ROS, and unfolded protein response gene sets were not found to be enriched in the high bile acid metabolism group, despite the expectation that oxidative stress-induced apoptosis would lead to improved survival. Several metabolic pathways and pathways associated with bile acid production and regulation were enriched in this group. On the other hand, Ki67 and nuclear grade were higher, and several cell proliferation-related gene sets were upregulated in the low bile acid metabolism group, especially the G2M checkpoint in all cohorts. In association with the higher cell proliferation, the low bile acid metabolism group showed higher mutation load, immune activation, and infiltration of anti-cancer immune cells. We further investigated that the composition of the microbiome in each group and four species that demonstrated significant abundance in the high bile acid metabolism group and three species in the low bile acid metabolism group. Surprisingly, almost all the cell proliferation-related gene sets from Hallmark were enriched in the three microorganisms-rich groups specific for low bile acid metabolism breast cancer. This was not the case for the microorganisms specific to high bile acid metabolism. Conclusions: Clinical relevance of bile acid metabolism in breast cancer is that low bile acid metabolism with abundant Lactobacillus, Ruegeria, and Marichromatium is associated with highly proliferative cancer and worse survival, rather than the growth suppression effect of bile acids.
Unpacking low-value castration practices using behavior specification to guide de-implementation in prostate cancer care.
Authors: Ted A. Skolarus, Jane Forman, Jordan B. Sparks, Tabitha Metreger, Sarah T. Hawley, Megan Veresh Caram, Lesly Ann Dossett, Angela Larkin, Alan Paniagua Cruz, Danil V. Makarov, John T. Leppert, Jeremy B. Shelton, Kristian D. Stensland, Brent K. Hollenbeck, Vahakn Shahinian, Daniela A. Wittmann, Varad Deolankar, S. Sriram
Journal: Journal of Clinical Oncology (2022)

e17055 Background: Many men with prostate cancer will be exposed to ADT at some point during cancer survivorship. Unfortunately, ADT overuse in low-value scenarios is not uncommon (e.g., monotherapy in localized prostate cancer, biochemically-recurrent non-metastatic disease) resulting in more harms than benefits. We conducted an innovative survey study to unpack ADT overuse to inform behavior change and de-implementation strategies. Methods: Our survey used the Theoretical Domains Framework (TDF), and the Capability, Opportunity, Motivation – Behavior (COM-B) Model. The survey was fielded to the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on their likelihood of stopping ADT monotherapy in the case of a localized prostate cancer patient presenting to their office (yes/probably yes, probably no/no), and characterized Likert scale responses to 7 COM-B statements. We used multivariable logistic regression to identify associations between stopping ADT and COM-B responses across a dichotomized Likert scale of “strongly disagree/disagree/neutral” and “agree/strongly agree.”. Results: Our survey was completed by 84 respondents (13% response rate), with 27% indicating ‘probably no’/‘no’ to stopping low-value ADT monotherapy in the case of a localized prostate cancer patient presenting to their office. Our multivariable model identified 2 COM-B statements significantly associated with lower likelihood of stopping low-value ADT. Conclusions: Using an innovative, behavioral theory-informed survey, we identified that providers less likely to stop low-value ADT had greater concern about patient worry and were more interested in providing ADT recommendations consistent with peers, informing de-implementation strategy selection. Clinical trial information: MCT03579680. [Table: see text]